Michael S. Okun, M.D. - US grants

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) has been demonstrated to be effective in the treatment of the cardinal motor symptoms of Parkinson's disease (PD) (tremor, rigidity, and bradykinesia). Both STN and GPi DBS have been documented to be effective in treating parkinsonian motor signs. Due to early limited reports, which suggest more robust improvements in UPDRS motor scores, and the ability to reduce parkinsonian medication with STN, but not GPi, STN has been the preferred target of most centers. There is, however, increasing evidence that STN DBS may be associated with a significant number of mood and cognitive changes. Because of the small size of the STN (158mm3), stimulation within the sensori-motor area can result in spread to limbic and associative areas of STN as well as to surrounding structures and fiber systems that may also affect mood and cognition. Since the Gpi (478mm3) is significantly larger than STN, a lead can be placed in the sensorimotor territory of the GPi with less likelihood of current spread to non-motor portions of the GPi or to adjacent structures and fiber systems that can adversely change mood and cognition. In this proposal we will 1) Characterize and compare the mood and cognitive changes associated with STN and GPi DBS, 2) delineate regions within or around the STN and GPi that are associated with specific mood and cognitive changes during DBS in these regions, and 3) assess the relative effect of right versus left STN or GPi stimulation on mood and cognition. This study will characterize the types and incidence of mood and cognitive changes that occur during stimulation in STN and GPi. It will also compare the relative changes in mood and cognition that occur in each site and examine the role of lead location in mediating them. The research is part of a five-year plan for training and career development for the Principal Investigator. This proposal includes active and experienced mentoring, access to diverse resources, and a scientific environment suited specifically for the development of the PI as an independent physician scientist.

DESCRIPTION (provided by applicant): Improved treatments for medication refractory Tourette's Syndrome (TS) are needed to address a subset of severely affected patients. Chronic high frequency deep brain stimulation (DBS) has recently emerged as a possible therapeutic option in refractory cases incapacitated by their tics. Although DBS has been utilized for addressing basal ganglia disorders such as Parkinson disease, essential tremor, and dystonia, these diseases differ fundamentally from TS. The symptoms of TS are characteristically paroxysmal and change their character over time. TS can also include a wide spectrum of behavioral symptoms. One brain area, the centromedian thalamus (CM) has shown the most promise (N>20) as a therapeutic target for DBS in refractory TS. Nevertheless, there is room for improvement. One drawback of previous studies may be that stimulation was delivered in a "continuous" mode. We hypothesize that a different stimulation pattern, either "scheduled" (delivered at specific intervals and for specified amounts of time) or "responsive" (timed to coincide with occurrence of tics), may produce more optimal results. Potential advantages of scheduled and responsive brain stimulation over continuous DBS include: 1) the ability to address the paroxysmal nature of the symptoms of TS;2) a strategy that may prevent or limit tolerance;and 3) not negatively impact normal inter-tic functioning. This pilot study will investigate the efficacy and tolerability/safety bilateral "scheduled" CM stimulation using a novel DBS device, the Responsive NeuroStimulator (RNS), in six adult subjects with severe and intractable TS (specific aim 1). Activation of the device will be at either one or two months (staggered onset) following implantation under randomized double-blind conditions. Outcome will be assessed at six months of chronic stimulation using standardized tic and related functional measures by blinded evaluators. The RNS device is currently under testing for epilepsy and was selected primarily because of its flexibility in delivering different stimulation patterns including the potential for responsive stimulation based on ongoing intracranial recordings. An additional advantage of RNS for the TS patient is that it is self-contained in the skull and brain and the system contains no tunneled neck connector wire and no chest pacemaker device. This feature may help to limit device related fractures due to tics involving the neck region as well as lessen provocation of self-injurious behaviors aimed at the pacemaker site. Using the recording mode of the device, we will study intra-operative and post-operative physiology of tics in specific aim 2. The data gleaned from these studies will be used for an exploratory trial of "responsive" brain stimulation (specific aim 3) in the same cohort of subjects. This is a pilot study of the benefits and safety of a novel deep brain stimulation (DBS) device in six adult subjects with severe and intractable Tourette Syndrome (TS). Although neurosurgery should be considered a last resort in TS, refinements in DBS as proposed herein may better tailor the stimulation parameters to the symptoms of patients with TS who are otherwise incapacitated or at risk of further injury by their tics.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deep brain stimulation-DBS of the subthalamic nucleus-STN and globus pallidus interna (GPi) has been demonstrated to be effective in the treatment of the cardinal motor signs of Parkinson's disease-PD: tremor, rigidity, and bradykinesia. Due to early limited reports, which suggest more robust improvements in UPDRS motor scores, and the ability to reduce parkinsonian medication with STN, but not GPi, STN has been the preferred target of most centers. There is increasing evidence that STN DBS may be associated with a number of mood and cognitive changes. Because of the small size of the STN, 158mm3, stimulation within the sensori-motor area can result in spread to limbic and associative areas of STN as well as to surrounding structures and fiber systems that may also affect mood and cognition. Since the GPi, 478 mm3, is significantly larger than the STN, a lead can be placed in the sensorimotor territory of the GPi with less likelihood of current spread to non motor portions of the GPi or to adjacent structures and fiber systems that can adversely change mood and cognition. The aim of this study is to carry out a prospective clinical trial investigating the effect of STN and GPi DBS on mood and cognitive function. This study will characterize the types and incidence of mood and cognitive changes that occur during stimulation in STN and GPi. It will also compare the relative changes in mood and cognition that occur in each site and examine the role of lead location in mediating them.

DESCRIPTION (provided by applicant): Tourette syndrome (TS) is in a class of neuropsychiatric disorders referred to as "tic disorders" which are characterized by involuntary, often repetitive behaviors that can be disruptive, inappropriate, and self-injurious. While recent work in the pathophysiology [1] and functional imaging [2] has provided new knowledge into the neural circuitry of TS, there remains a formidable knowledge gap in understanding the activity of single neurons, neuronal populations, and local field potentials that may be related to human tic generation. The goal of this project is to accelerate of the characterization of human physiology in patients with TS through the utilization of microelectrode based physiological techniques that can be coupled to time-synchronized recordings of tic phenomenology/appearance. This procedure of coupling the high-resolution neuronal recordings with behavior is not common in TS because of both the lack of availability to intracranial recordings in TS patients and also expertise to perform such work. Accessing Deep Brain Stimulation (DBS) patients through this grant will offer a unique opportunity to quantify the neural representation of tics. Our interdisciplinary team has demonstrated feasibility and has particular expertise in neural coding, novel neural/behavioral experimental design, neurology of TS, and DBS surgery for TS (currently the only center in the US with a FDA IDE to perform TS DBS).

? DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has tremendous potential to improve the lives of patients with a wide range of chronic illnesses. Good outcomes from DBS for Parkinson's disease (PD) are strongly correlated to accurate electrode placement and to careful post-operative selection of stimulation parameters (voltage, pulse width, frequency, active electrode contact(s), among others). Although DBS is beneficial for a variety of disorders, a persistent problem has been extensive, costly programming time after the electrode leads are implanted. This is largely because there are very few tools available to assist clinicians in this process, and as a result DBS programming can require a significant degree of experience and expertise, as well as a substantial amount of time for the clinician to search for optimal device settings. Over the last few years computational models have been developed to predict and visualize the effects of DBS based on the neuroanatomy of individual patients. Recently these models have shown promise for improving the efficiency of DBS programming, and have been incorporated into a clinical decision support system. The long-term goal of this research is to improve the lives of patients with neurological disease that are treated with DBS. The objective of this application is to prospec- tively test the use of DBS clinical decision support tool in post-operative clinical care. The central hypothesis is that the use of a DBS clinical decision support system for individual patient management will enable consider- able time savings and reduced burden on patients and caregivers. This hypothesis has been formulated from pilot studies that have shown dramatic decreases in DBS programming time compared to standard care for clinicians who used an iPad-based decision support system (99% time savings from over 4 hours to 2 minutes). The rationale for the proposed research is that computational models, clinical informatics, and mobile computing devices can be used to enable DBS management in a way that has never before been possible. Guided by strong preliminary data, this hypothesis will be tested in two specific aims: 1) Measure the effective- ness of DBS decision support system in an established PD clinic; 2) Measure the effectiveness of DBS deci- sion support system by home health nurses. Under the first aim we will compare programming time and clinical outcomes for patients managed using the clinical decision support system compared to standard care. Under the second aim we will assess the effects of the system on patient and caregiver strain when used by home health nurses. This approach is innovative because it provides an iPad-based clinical decision support applica- tion (app) to enable nurses and physicians to quickly focus on stimulation settings that are likely to be most effective. The proposed research is significant because it will provide powerful tools to the health care provid- ers who will be able to provide the greatest benefit for DBS patients. The knowledge gained could enable a future model for DBS management where care is provided in both clinical and home settings by skilled nurses who use expert systems for guidance.

? DESCRIPTION (provided by applicant): Tourette syndrome (TS) and disorders involving tic are highly prevalent and socially embarrassing. There are a group of TS sufferers with motor and vocal tics that are resistant to medication and behavioral intervention. Deep brain stimulation (DBS) has emerged as a highly efficacious treatment option for addressing motor and vocal tics in a select group of appropriately screened cases. The proposed research will directly address the important knowledge gaps in TS physiology and TS DBS. These gaps include a need to characterize the pathophysiological signals related to tics and the modulation of physiology by DBS therapy. In Aim 1, we will correlate individual tic expression with local fiel potential (LFP) activity in the human centromedian (CM) thalamic nucleus region and precentral gyrus (motor cortex) using next generation DBS devices capable of chronic LFP recordings. We will also study thalamocortical network interactions leading to tics. Our preliminary data from two subjects have revealed that low-frequency activity in the CM thalamus and beta rhythm suppression in the motor cortex correlate with the occurrence of tics, and that these features can be differentiated from the neural correlates of voluntary movements. In Aim 2, we will determine how LFP physiology changes following DBS therapy and clinical improvement. Our preliminary data from five subjects, treated with bilateral centromedian (CM) thalamic region DBS, (from recently completed NIH R34 and R21 grants) demonstrated the presence of both a measurable clinical effect and quantifiable physiological changes (decreases in low frequency power). Understanding how DBS modulates brain activity to reduce TS symptoms, could provide a neuromarker to guide clinical programming and potentially facilitate faster clinical relief. The overarching goal of the proposed project will be to generate the physiological dataset required to fill these knowledge gaps and to move the field toward responsive stimulation.

Magnetic resonance imaging (MRI) is the most widely used diagnostic imaging tool for detecting neurodegenerative disorders such as Parkinson's Disease. This project will develop new automated methods for detecting subtle effects that can be revealed by MRI, including changes in water diffusional properties of human brain tissue, and functional brain activity. To assess the deviation from the normal brains, a computationally efficient algorithm will be developed to construct a population-specific brain structural template from a normal brain population. Further, a new algorithm will be developed to facilitate the detection of Parkinson's using diffusion MRI data. Finally, novel algorithms for establishing the correlation between the information derived from diffusion and functional MRI data will be developed, enabling prediction of functional activity given the anatomical information and vice-versa. Inferring such a correlation will make it possible to predict functional changes due to changes in tissue microstructure caused by neurodegenerative disorders and vice-versa.

In summary, the precise project goals are: (i) To develop a computationally efficient template brain map construction algorithm for features derived from diffusion MRI. In this context, the ensemble average propagator (EAP), which captures both orientation and shape information of the diffusion process at each voxel in the diffusion MRI data, is proposed. Validation of the constructed template will be performed using standard evaluation metrics for template-based segmentation. (ii) To develop novel methods to automatically discriminate between control and Parkinson's groups using the EAP fields as well as Cauchy deformation tensors (that capture the changes in EAP fields). Validation of the classifier will be achieved using the standard leave-k-out strategy. (iii) To develop a novel algorithm for kernel-based nonlinear regression between EAP fields derived from diffusion MRI and scalar-valued fields derived from functional MRI activation maps. The algorithm will be able to predict the level of activation given the EAP fields and vice-versa. These predictions will be validated using a priori labeled data sets. Predicting functional responses from structural information and vice-versa will significantly impact treatment planning of patients with Parkinson's Disease and other neurodegenerative disorders. The multidisciplinary nature of this project will provide the opportunity to collectively train graduate students from diverse backgrounds in the STEM related fields of this project.

Abstract The next generation of academic leaders in Neurology and Neurosurgery residency programs will require expert research training and mentorship in order to achieve a balanced academic career. Unfortunately, most training programs are better suited to develop the clinician and not prepared to mentor the clinician-researcher or to offer him/her the dedicated time necessary to develop an academic research project. There is a danger of the disappearing clinician-scientist and this danger in a reality in many institutions based on an ever increasing patient care demand and a shortage of neurologists and neurosurgeons. The University of Florida neurology and neurosurgery residency programs have adopted an infrastructure to identify resident researchers early in their training and to advance them toward K awards. This early identification coupled with a milestone driven approach has provided a formula for the success of residents interested in research career paths. This NINDS R25 application from the University of Florida (UF) will focus on the development of a comprehensive early research program to meaningfully engage neurology and neurosurgery residents in research from day 1 of their internship all the way through their residency, fellowship, and successful K award application. This project will provide the potential UF R25 individual applicant access to an ideal research environment with protected time, coursework, mentorship and a strong institutional commitment. UF offers outstanding basic/translational laboratory experiences, clinical research, research facilities, and an expert mentor-mentee experience. Potential R25 enrollees at UF will have access to a freestanding neuromedicine hospital, multiple interdisciplinary clinics with significant research/clinical trials infrastructure, and the core facilities of the McKnight Brain Institute. The potential R25 participant will be identified early in their residency training, placed on a research track and mentored toward a dedicated research experience and ultimately a NIH K award.

PROJECT SUMMARY Here, our multidisciplinary group with expertise in movement disorders and motor physiology, proposes to study the effects of deep brain stimulation of the ventralis intermedius nucleus (VIM DBS) on balance and gait tasks of patients with Essential Tremor (ET). Although VIM DBS is effective in controlling upper limb tremor, it does not address balance and gait disturbances in ET. This is a significant problem because balance and gait disturbances occur in >40% of ET patients, who exhibit lower quality of life and increased risk for falls and mortality. The inability to mitigate balance and gait disturbances may be a consequence of the DBS targeting a location within the VIM that reduces hand tremor but not tremor relevant to balance and gait. Our preliminary data show that only when VIM DBS reduced midline tremor, balance and gait improved. These findings are based on measurements of midline tremor with sensitive accelerometers during balance and gait tasks. In contrast, current measures of midline tremor are based on qualitative clinical assessments and have never been performed during balance and gait tasks. Thus, current measures of midline tremor are not task-relevant and lack sensitivity. In this proposal, therefore, we will determine if midline tremor is a marker for balance and gait impairments using sensitive accelerometry and electromyography (EMG) of postural muscles and innovative analyses. We will test the central hypothesis that when thalamic neurostimulation reduces midline tremor amplitude, balance and gait improve and risk for falls decreases. In Aim 1, we propose to characterize the effects of neurostimulation on tremor at multiple body locations during static and dynamic balance tasks and during straight and obstacle overground walking tasks (task-relevant tremor). We will quantify tremor using sensitive accelerometers and EMG when ET patients perform balance and gait tasks with their DBS ON or OFF. We test the hypothesis that only the VIM DBS-induced reduction of midline tremor will relate to balance and gait improvements. In Aim 2, we examine the association between the change in risk for falls (pre/post DBS surgery) and the change in tremor quantified at various locations during balance and gait tasks (DBS ON/OFF). We will quantify the risk for falls before and after DBS surgery by using the Activities Specific Balance Confidence scale (ABC), a validated and sensitive scale for risk for falls. In addition, we will quantify performance during the Berg Balance Test (BBS) and Timed Up and Go Test (TUG) with DBS ON and OFF. We will test the hypothesis that a greater VIM DBS-induced reduction in midline tremor amplitude will relate to decreased risk for falls. If successful, the outcomes of this proposal are clinically impactful because they will advance the use of DBS for treating balance and gait disturbances in ET and in other disorders.

PROJECT SUMMARY Tourette syndrome (TS) is a continuous lifelong condition that is highly prevalent, socially disabling, and in some severe cases, physically injurious. DBS has emerged as a promising treatment option for addressing uncontrollable tics in medically resistant and severe cases of TS frequently involving self-injurious behavior. We have undertaken a major informatics initiative by establishing the International TS DBS Registry and Database, a multi-country consortium that has captured long term outcomes of 277 TS DBS patients representing 50-75% of all TS DBS cases worldwide. From these outcomes, two deep brain targets have emerged as potentially effective: the centromedian nucleus region (CM) of the thalamus, and the anterior globus pallidus internus (aGPi). However, our current understanding of tic generation is limited by many factors including a lack of animal models for TS, apparently normal brain structure on structural imaging, and the impracticality of studying involuntary motor tics with functional imaging. Next generation closed-loop DBS systems can record brain activity in patients with TS and identify the neurophysiological correlates of tics. Moreover, these devices can deliver stimulation in response to a patient's symptomatic state. Our overall goal is to develop neurophysiology driven and connectivity-guided closed-loop DBS systems for the improved treatment of TS. To this end, we will implant 8 medically resistant TS patients with bilateral leads in the CM and aGPi. In Aim 1, we will identify structural network projections from CM and aGPi to guide pre-operative surgical planning and post-operative selection of stimulation parameters. In Aim 2, we will identify neurophysiologic correlates of tic genesis in the CM and aGPi. We will also study thalamo-pallidal network interactions leading to and during tics. In Aim 3, we will test the feasibility, safety, and efficacy of closed-loop TS DBS. We expect that closed-loop stimulation will provide more effective and personalized treatment options with longer battery life and fewer adverse effects.